Use of Nordihydroguaiaretic Acid Derivatives in the Treatment of Drug Resistant Cancer, Viral and Microbial Infection

Abstract

Compositions and methods for using nordihydroguaiaretic acid (NDGA) derivatives for preventing the expression of MDR-1 gene and the synthesis of PgP protein or reversing multiple drug resistance in cells, and for using NDGA derivatives in combination with additional chemotherapeutic agents to treat drug resistant cancer and infections.

1 - 57 . (canceled) 
     
     
         58 . A method for preventing at least one of synthesis and function of drug transporter protein Pgp in a cell, the method comprising administering an NDGA derivative or a physiologically acceptable salt thereof, the NDGA derivative having the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of HO—, CH 3 O—, CH 3 (C═O)O—, an amino acid residue, a substituted amino acid residue and a saccharide residue; the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms, with the proviso that
 i) at least one of R 1 -R 4  comprises an amino acid residue or substituted amino acid residue, or 
 ii) one of R 1 -R 4  comprises a saccharide residue. 
 
     
     
         59 . The method according to  claim 58  wherein at least one of R 1 -R 4  comprises a residue of an amino acid having at least two —CH 2 — groups present between an amino group and a carboxyl group. 
     
     
         60 . The method according to  claim 59  wherein R 1 -R 4  each comprises —CO—(CH 2 ) 3 —N—(CH 3 ) 2 . 
     
     
         61 . The method according to  claim 58  wherein one of R 1 -R 4  comprises a monosaccharide residue or disaccharide residue. 
     
     
         62 . The method according to  claim 58  wherein at least one of R 1 -R 4  comprises an amino acid residue, substituted amino acid residue or saccharide residue, wherein the amino acid residue, substituted amino acid residue or saccharide residue is joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms. 
     
     
         63 . The method according to  claim 62  wherein R 1  is —O—CH 2 —CH 2 -maltose or —O—CH 2 —CH 2 -galactose, and R 2 -R 4  are each —OCH 3 . 
     
     
         64 . The method according to  claim 58  wherein synthesis of Pgp is caused by a chemotherapeutic agent. 
     
     
         65 . The method according to  claim 64  wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin, vinblastine, paclitaxel, and vincristine. 
     
     
         66 . The method according to  claim 58  wherein the cell is a tumor cell. 
     
     
         67 . The method according to  claim 58  wherein the cell is an infectious microorganism. 
     
     
         68 . The method according to  claim 67  wherein the cell is a virus, bacterium, parasite or fungus. 
     
     
         69 . The method according to  claim 58  wherein the NDGA derivative prevents chemical induction of multiple drug resistance gene 1 (MDR1) expression in a cell. 
     
     
         70 . The method according to  claim 58  wherein the NDGA derivative prevents expression of MDR1 in a cell. 
     
     
         71 . A method of treating cancer, the method comprising administering an NDGA derivative or physiologically acceptable salt thereof in combination with at least one secondary chemotherapeutic agent to treat cancer, the NDGA derivative having a formula 
       
         
           
           
               
               
           
         
       
       wherein
 i) at least one of R 1 -R 4  comprises an amino acid residue having at least 2 —CH 2 — groups present between an amino and a carboxyl group, or comprises a substituted amino acid residue having at least 2 —CH 2 — groups between an amino and a carboxyl group, and the remaining R groups are independently selected from HO—, CH 3 O— and CH 3 (C═O)O—; or 
 ii) one of R 1 -R 4  comprises a saccharide residue and the remaining R groups are selected from HO—, CH 3 O— and CH 3 (C═O)O—; 
 
       the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms. 
     
     
         72 . The method according to  claim 71  wherein at least one of R 1 -R 4  comprises a residue of an amino acid having at least two —CH 2 — groups present between the amino group and the carboxyl group. 
     
     
         73 . The method according to  claim 72  wherein R 1 -R 4  each comprises —CO—(CH 2 ) 3 —N—(CH 3 ) 2 . 
     
     
         74 . The method according to  claim 71  wherein one of R 1 -R 4  comprises a monosaccharide residue or disaccharide residue. 
     
     
         75 . The method according to  claim 74  wherein the monosaccharide or disaccharide residue is joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms. 
     
     
         76 . The method according to  claim 75  wherein one of R 1 -R 4  is —O—CH 2 —CH 2 — maltose or —O—CH 2 —CH 2 -galactose, and the remainder of R 1 -R 4  are —OCH 3 . 
     
     
         77 . The method according to  claim 71  wherein the secondary chemotherapeutic agent is selected from the group consisting of doxorubicin, vinblastine, paclitaxel, and vincristine. 
     
     
         78 . The method according to  claim 71  wherein the cell is a tumor cell. 
     
     
         79 . The method according to  claim 71  wherein the cell is an infectious microorganism. 
     
     
         80 . The method according to  claim 79  wherein the cell is a virus, bacterium, parasite or fungus. 
     
     
         81 . The method according to  claim 71  wherein the molar ratio of the NDGA derivative to the secondary chemotherapeutic agency is about 20:1. 
     
     
         82 . The method according to  claim 71  wherein the molar ratio of the NDGA derivative to the secondary chemotherapeutic agency is about 2.4:1. 
     
     
         83 . A method of preventing or overcoming multiple drug resistance in a cancer cell, the method comprising the administration of an NDGA derivative or physiologically acceptable salt thereof to the cancer cell, the NDGA derivative having a formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of HO—, CH 3 O—, CH 3 (C═O)O—, an amino acid residue, a substituted amino acid residue and a saccharide residue; the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms, with the proviso that
 i) at least one of R 1 -R 4  comprises an amino acid residue or substituted amino acid residue, or 
 ii) one of R 1 -R 4  comprises a saccharide residue. 
 
     
     
         84 . The method according to  claim 83  wherein at least one of R 1 -R 4  comprises a residue of an amino acid having at least two —CH 2 — groups present between the amino group and the carboxyl group. 
     
     
         85 . The method according to  claim 83  wherein R 1 -R 4  each comprises —CO—(CH 2 ) 3 —N—(CH 3 ) 2 . 
     
     
         86 . The method according to  claim 83  wherein one of R 1 -R 4  comprises a monosaccharide or disaccharide residue. 
     
     
         87 . The method according to  claim 86  wherein at least one of R 1 -R 4  is —O—CH 2 —CH 2 -maltose or —O—CH 2 —CH 2 -galactose, and the remainder of R 1 -R 4  are —OCH 3 . 
     
     
         88 . The method according to  claim 83 , further comprising administering a drug selected from the group consisting of doxorubicin, vinblastine, paclitaxel, and vincristine. 
     
     
         89 . The method according to  claim 83  wherein the cell is a tumor cell. 
     
     
         90 . The method according to  claim 89  wherein the tumor cell is a human cancer cell. 
     
     
         91 . The method according to  claim 90  wherein the cancer is selected from the group consisting of breast cancer, lung cancer, melanoma, ovarian cancer, multiple myeloma, and Non-Hodgkin's Lymphoma. 
     
     
         92 . The method according to  claim 58  wherein the cell is the cell of a nonhuman animal. 
     
     
         93 . The method according to  claim 92  wherein the animal is a mammal. 
     
     
         94 . The method according to  claim 71  wherein the cancer is a cancer of a nonhuman animal. 
     
     
         95 . The method according to  claim 94  wherein the animal is a mammal. 
     
     
         96 . The method according to  claim 83  wherein the cell is the cell of a nonhuman animal. 
     
     
         97 . The method according to  claim 96  wherein the animal is a mammal. 
     
     
         98 . A method of overcoming drug resistance in a microorganism, comprising administering to the microorganism or a host containing the microorganism an effective amount of an NDGA derivative or a physiologically acceptable salt thereof, the NDGA derivative having the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of HO—, CH 3  O—, CH 3 (C═O)O—, an amino acid residue, a substituted amino acid residue and a saccharide residue; the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms; with the proviso that
 i) at least one of R 1 -R 4  comprises an amino acid residue or substituted amino acid residue, or 
 ii) one of R 1 -R 4  comprises a saccharide residue. 
 
     
     
         99 . The method of  claim 98  wherein the microorganism is selected from the group consisting of a virus, a bacterium, a parasite and a fungus. 
     
     
         100 . A method of treating a drug-resistant infection in an animal, comprising administering to the animal, along with at least one therapeutic agent to which the infection is resistant, an effective amount of a compound, or a physiologically acceptable salt thereof, of formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of HO—, CH 3 O—, CH 3 (C═O)O—, an amino acid residue, a substituted amino acid residue and a saccharide residue; the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms, with the proviso that
 i) at least one of R 1 -R 4  comprises an amino acid residue or substituted amino acid residue, or 
 ii) one of R 1 -R 4  comprises a saccharide residue. 
 
     
     
         101 . The method of  claim 100  wherein the infection is a viral, bacterial, parasitic or fungal infection. 
     
     
         102 . A composition comprising a compound of formula 
       
         
           
           
               
               
           
         
       
       or a physiologically acceptable salt thereof, wherein
 i) at least one of R 1 -R 4  comprises a β-amino acid residue linked to the phenyl ring through an oxygen atom; or 
 ii) one of R 1 -R 4  comprises a saccharide residue, optionally linked to the phenyl ring through an oxygen atom and 1-10 —CH 2 — groups; and 
 
       the remainder of R 1 -R 4  are —OCH 3 . 
     
     
         103 . The composition of  claim 102  wherein one of R 1 -R 4  comprises a monosaccharide residue or disaccharide residue. 
     
     
         104 . The composition of  claim 103  wherein the saccharide residue is selected from the group consisting of a residue of glucose, galactose, mannose, fucose, glucosamine, galactosamine and derivatives thereof on which the —OH groups or amino groups are modified by attachment of or replacement with substituents selected from O-methyl, O-acetyl, amino, carboxyl, lower alkyl, lower acyl, phospho and sulfo groups. 
     
     
         105 . The composition of  claim 102  wherein one of R 1 -R 4  comprises an oligosaccharide residue consisting of at least two sugars of the same or different kinds. 
     
     
         106 . The composition of  claim 103  wherein the compound is maltose-M 3 N or galactose-M 3 N. 
     
     
         107 . The composition of  claim 102  wherein at least one of R 1 -R 4  comprises a amino acid residue. 
     
     
         108 . The composition of  claim 102  comprising 5-((2S,3R)-4-{3,4-bis[4-(dimethylamino)butanoyloxy]phenyl}-2,3-dimethylbutyl)-2-[4-(dimethylamino)butanoyloxy]phenyl 4-(dimethylamino)butanoate or 5-((2S,3R)-4-{3,4-bis[4-(dimethylamino)propanoyloxy]phenyl}-2,3-dimethylbutyl)-2-[4-(dimethylamino)propanoyloxy]phenyl 4-(dimethylamino)propanoate. 
     
     
         109 . The composition of  claim 102  that additionally comprises a secondary chemotherapeutic agent. 
     
     
         110 . The composition of  claim 109  wherein the secondary chemotherapeutic agent is selected from the group consisting of doxorubicin, vinblastine, paclitaxel, and vincristine. 
     
     
         111 . The composition of  claim 109  wherein the NDGA derivative and the secondary chemotherapeutic agent have a molar ratio of about 2:1 to about 100:1. 
     
     
         112 . A composition comprising an NDGA derivative, or a physiologically acceptable salt thereof, and a secondary chemotherapeutic agent, the NDGA derivative having the formula 
       
         
           
           
               
               
           
         
       
       wherein
 i) at least one of R 1 -R 4  comprises an amino acid residue having at least 2 —CH 2 — groups present between an amino and a carboxyl group, or comprises a substituted amino acid residue having at least 2 —CH 2 — groups between an amino and a carboxyl group, and the remaining R groups are independently selected from HO—, CH 3 O— and CH 3 (C═O)O—; or 
 ii) one of R 1 -R 4  comprises a saccharide residue and the remaining R groups are selected from HO—, CH 3 O— and CH 3 (C═O)O—; 
 
       the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms. 
     
     
         113 . The composition of  claim 112  wherein the NDGA derivative and the secondary chemotherapeutic agent have a molar ratio of about 2:1 to about 100:1. 
     
     
         114 . The composition of  claim 112  comprising M 4 N or maltose-M 3 N and paclitaxel in a molar ratio of about 20:1. 
     
     
         115 . The composition of  claim 112  comprising M 4 N or maltose-M 3 N and doxorubicin in a molar ratio of about 2.4:1. 
     
     
         116 . A method for determining an optimum dosage combination of an NDGA derivative, or a physiologically acceptable salt thereof, and a secondary chemotherapeutic agent for treating a cancer, the NDGA derivative having the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of HO—; CH 3 O—; CH 3 (C═O)O—; an amino acid residue; a substituted amino acid residue; a saccharide residue; the amino acid residue, substituted amino acid residue or saccharide residue being optionally joined to the phenyl ring by a linker selected from the group consisting of at least one of an oxygen atom and 1-10 carbon atoms; the method comprising
 (a) administering a series of compositions of varying dosages of the NDGA derivative and the secondary chemotherapeutic agent to a culture of cancer cells; 
 (b) measuring the growth rate of the cells; 
 (c) using an isobologram method or combination index method to determine the optimal combination dosage to achieve comparable efficacy with suboptimal concentrations for both the NDGA derivative and the secondary chemotherapeutic agent. 
 
     
     
         117 . A composition comprising the optimal dosage combination of  claim 116 . 
     
     
         118 . A method of treating cancer comprising administration of an effective amount of the composition of  claim 117  to an individual in need of treatment.